JPH10101525A - Stabilization of unstable retinoid in oil-in-water type emulsion for skin care composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject emulsion useful as a skin care composition, capable of stabilizing an unstable retinoid by using a specific oil phase and combining the oil phase with a barrier layer composed of a prescribed solid compound. SOLUTION: This emulsion comprises (A) an oil phase comprising 0.1-50wt.% based on the emulsion of oil drops constituted of a fluid oil and 0.01-10wt.% based on the emulsion of a retinoid selected from the group consisting of retinol, retinyl acetate and retinyl propionate, (B) 50-98wt.% based on the emulsion of an aqueous phase and (C) 1-20wt.% based on the emulsion of a barrier component containing a crystal forming compound and a crystal fixed size compound. The average size of the individual crystals in the barrier layer is in the range of 1-50μm, the ratio of the individual sizes of the oil drops to the individual crystals in the barrier layer is in the range of 5:1 to 100:1 and the melting point of the fluid oil and the barrier component is in the range of 40-100 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a skin care composition containing retinol or a short-chain ester thereof in an oil-in-water emulsion.

[0002]

BACKGROUND OF THE INVENTION Natural and synthetic vitamin A derivatives are widely used in the treatment of various skin disorders and are used as skin repair or regenerators. Retinoic acid has been used to treat various skin conditions such as acne, wrinkles, psoriasis, age spots and discoloration.
See, for example, Vahlquist, A. et al.
J. et al. Invest. Dermatol. Vol. 9
4, Holland D.C. B. And Cunlife, W.W. J. (1990), 4
96-498; Ellis, C.E. N.
"Pharmacology of Retinols in.
Skin (Pharmacology of Retino)
ls in Skin) ", Basel,
Karger, Vol. 3, (198
9) pp. 249-252; Lowe,
N. J. "Pharmacology of Retinols in Skin", Vol. 3 (1989), 240-
248 pages; PCT Patent Application No. (WO) 93/197
See No.43.

[0003] The use of retinol or short-chain esters of retinol is believed to be advantageous over retinoic acid. Retinol is an endogenous compound that occurs naturally in the human body and is essential for normal epithelial cell differentiation. Short-chain esters of retinol hydrolyze in vivo to yield retinol. Retinol and retinyl esters are believed to be safer than retinoic acid.

[0004] Long chain retinyl esters, especially retinyl palmitate, are widely used in skin cosmetic compositions. Such compositions include, for example, Chesbrough-Pond '
Age Defying Complex ^R manufactured by s)
And an oil-in-water emulsion such as However, with the involvement of the present invention, it has been found that retinol or short chain esters of retinol are more potent than long chain esters of retinol, such as retinyl palmitate (see Example 7). It is believed that retinyl palmitate is not hydrolyzed in vivo to retinol and / or does not penetrate the skin.

[0005] Unfortunately, retinol and short-chain retinyl esters are more unstable than retinoic acid or long-chain retinyl esters. Idson, "Vitamins and the Skin (Vitamins and
the Skin) ", Cosmetics & Toiletries
s), Vol. 108, December 1993, 79-94
Page, Allured PublishingCorporation
p. Hoffman-La Roche (1993);
man-La Roche) Inc. , Data Sheet, “Vitamin A-The 'Normalizer”
iser ') ”, Roche Vitamins & Fine Chemicals (Roche Vitamins & Fine)
Chemicals); Hoffman-La Roche In
c. Product Data (Product Data)
"Vitamin A Alcohol Blend (Vitamin
A Alcohol Blend) ". In particular, they decompose rapidly in the presence of water.

[0006] Anhydrous retinol-containing compositions are known in the art. For example, Dulac
See, U.S. Pat. No. 4,888,363 and Wilmott et al., U.S. Pat. No. 4,826,828. However, such compositions generally include a water-soluble skin benefit component,
In particular, even if such components are to be included in high amounts, they are not included.

[0007] Water-in-oil emulsions containing retinol in the oil phase are also known. For example, European Patent No. 440,
No. 398 (Johnson & Johnson),
International Patent Application (WO) 93/00085 (Johnson & Johnson) and European Patent Application 631,7
No. 72 (Johnson & Johnson). A series of disadvantages for both anhydrous compositions and water-in-oil emulsions are:
Because the continuous phase is the oil phase, it is oily and less attractive as a cosmetic than an oil-in-water emulsion.

[0008]

Therefore, it is desirable to formulate retinol or short-chain esters of retinol into oil-in-water emulsions. However, in such systems (as compared to anhydrous or water-in-oil emulsions), stabilization of unstable retinoids in such systems is due to the greater exposure of the retinoid to the aqueous phase. Could not. For example, at page 1, lines 34-37, the retinoids in oil-in-water emulsions are "unstable ... and chemically decompose, and are therefore useless over time for their claimed use. (Are unstable ... an
d chemically degrade and
are, therefore, unavailable
over time fortheir alleg
ed utility) ", see EP 440,398. The International Patent Application (WO) 930085 is described on page 8,
In lines 2-7, the doctrine states: "For obvious reasons, stability satisfaction with commercial products is:
Achieved for certain retinoids only by utilizing a particular form of emulsion, i.e., a water-in-oil emulsion, and only by using a particular stabilizing system.
chare not clear unders
good, stability satisfacto
ry for a commercial produ
ct has beenachiable for
certain specific retinoi
ds only by utilizing a sp
unique form of emulsion,
i. e. water-in-oil, and then,
only by implementing a speci
fic sabilizing system). "

The present invention is directed, in part, to the use of a particular oil phase to form oil droplets containing labile retinoids to be solubilized and a barrier layer of crystals of a particular size for the oil droplets. The combination of several key parameters, such as using a selected combination of solid compounds to form a sulphate, can result in the unstable retinoid, i.e., retinol or its short chain ester, being stabilized in an oil-in-water emulsion. Based on discovery.

[0010] The solid compounds and / or oils used in the present invention to form oil droplets surrounded by a crystal barrier layer have been used in skin care compositions, for example, as emollients. Some of these compositions also include retinoids, more often retinoic acid or retinyl palmitate. For example, Romania Patents (RO) Nos. 92, 576, 93, 807, 84, 823; U.S. Pat.
No. 06,108 (Felty et al.); US Pat.
No. 80764 (Herzog); U.S. Pat.
No. 981,845 (Pereira); US Pat. No. 5,037,850 (Elliot et al.);
U.S. Pat. No. 4,333,924 (Bowley
U.S. Patent No. 5,492,894 (Bas
com et al.). However, such compositions are defined by the present invention as at least they are unstable retinoids (retinol or short-chain esters thereof) within the oil droplets surrounded by a crystalline barrier of defined size.
Is not contained. The prior art does not provide stable oil-in-water emulsions containing retinol or short-chain esters thereof.

[0011]

The present invention includes, in part, oil-in-water emulsions for skin conditioning, wherein the emulsion comprises: (a) 0.1 to 50% by weight of the emulsion; , Oil droplets composed of fluid oil, and 0.001 to 1 of emulsion
50 (b), the emulsion; - 0 weight%, retinol and retinol C ₂ -C ₃ (where the retinoid is solubilized in the oil) retinoid selected from the group consisting of esters include oil phase 98% by weight of an aqueous phase; and (c) from 1 to 20% by weight of the emulsion containing a barrier component, wherein the barrier component provides a crystalline barrier layer between the oil droplets and the aqueous phase. The size of the crystals in the barrier layer is in the range from 1 μm to 50 μm, as measured by a microscopic crystal sizing test (see below); and the size of the individual crystals in the barrier against the individual oils The ratio is 5:
And the melting point of the mixture of the fluid oil and the barrier component is in the range of 40C to 100C.

As used herein, the term "conditioning" refers to the prevention and treatment of dry skin, photodamaged skin, wrinkle appearance, age spots, aging skin, increased stratum corneum softness and generally a ruddy shine and Means enhancement of skin quality. This composition may be used to improve skin desquamation and epidermal differentiation.

According to the present invention, by devising an oil droplet containing an unstable retinoid to be solubilized and surrounded by a crystalline barrier of a defined size range,
The stability of the retinoid in the oil-in-water emulsion is substantially improved. The presence of oil droplets containing retinoids and surrounded by a crystal barrier, according to the invention, has a melting point,
It is ensured by choosing a stream oil and barrier components that meet the crystal size and solubility requirements described in more detail below.

DETAILED DESCRIPTION All amounts of invention, unless otherwise indicated, are by weight of the oil-in-water emulsion.

[0015] The oil-in-water emulsions included in the compositions of the present invention contain oil droplets in a continuous aqueous phase.

The oil droplets contain, as a first essential component, a retinoid selected from the group consisting of retinol and C ₂ -C ₃ esters of retinol. As described in Example 7, these compounds are more potent than retinyl palmitate.

The term "retinol" as used herein includes the following isomers of retinol: all-trans-retinol, 13-cis-retinol, 11-cis-
Retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all-trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, 9-cis-retinol. Most advantageous is all-trans-retinol due to its wide commercial availability.

Retinyl esters are esters of retinol. The term "retinol" is as defined above. Suitable retinyl esters for use in the present invention are C ₂ and C ₃ esters of retinol, also known as retinyl acetate and retinyl propionate. Retinyl acetate is the most potent
Particularly advantageous esters are the most commercially available and the least expensive. For the same reason, the most advantageous retinoid for use in the present invention is retinol.

Retinol or retinyl ester is added to the composition of the present invention in an amount of from 0.001 to 10% of the emulsion.
It is used in an amount of% by weight, preferably in an amount of 0.01 to 0.5% by weight, most preferably in an amount of 0.05 to 0.2% by weight.

The second essential component of the oil phase in the emulsion of the present invention is a stream oil. The oil phase in the emulsions of the present invention may be formed from a single compound or a mixture of compounds. The oil phase according to the invention must be liquid and capable of solubilizing the required amount of retinol or its C ₂ -C ₃ ester at the storage temperature (typically 25 ° C.). Further, the mixture of the oil phase and the barrier component must meet the melting point test described in more detail below. The term “fluid” as used herein means that at 25 ° C., at least 50% of the oil is liquid.

Suitable compounds for forming the oil phase include, but are not limited to, esters and hydrocarbons of fatty acids or fatty alcohols, preferably fatty acids or fatty alcohols, as long as they meet the melting point and solubility requirements described above. Monoesters. Most advantageously, the fluid oil is isostearyl palmitate, tridecyl salicylate, C ₁₂ -C
It is selected from the group consisting of ₁₅ octanoate, isopropyl stearate, isopropyl myristate, and isopropyl palmitate.

The oil droplets containing retinoids are present in the emulsion according to the invention in an amount of 0.1 to 50% by weight of the emulsion,
Preferably 1 to 30% by weight, most preferably 5 to 15% by weight
May be included.

The third essential component of the emulsion of the present invention is a barrier component. The term "barrier component" as used herein means a mixture of at least two compounds: the first compound is a compound used for the formation of crystals ("crystal-forming compound"); The second is the compound needed to control the size of the crystals ("crystal sizing compound"). With the involvement of the present invention,
When using only crystal-forming compounds, the crystals formed were too large (see Example 4) and the retinoids were found to be unstable in such compositions. In addition, it was found that the second crystal sizing compound could not form a crystal having a sufficient size by itself, but controlled the crystal size (see Example 5). The co-presence of a crystal forming compound and a crystal sizing compound is necessary to stabilize the retinoid.

The size of the crystals is important to ensure the stability of the emulsion of the invention. If the crystals surrounding the oil droplets are too large, the crystals will migrate from the oil / water interface,
Remains separately in the emulsion. If the crystals are too small, the exposure of the oil phase to water will increase. In both cases, the stability of the retinoid in the oil phase is diminished. The average size of individual crystals in the emulsion of the present invention is 1 μm to 5 μm, as measured by a microscope crystal sizing test.
It is in the range of 0 μm, preferably in the range of 1 μm to 20 μm and most preferably in the range of 5 μm to 10 μm. The properties and amounts of the components that make up the fluid phase and the crystal barrier determine the size of the crystals.

Microscope sizing test (Microscopic
Crystal Sizing Test The intended fluid and the compounds forming the barrier are co-melted in the same proportions as those intended for the final emulsion. One drop of the co-melt mixture is placed on a microscope slide with a coverslip. Observe the size and shape of the crystals under a microscope. The crystals should be small and relatively smooth (not like sharp needles). The size is measured by taking a micrograph, measuring the crystal with a ruler, and taking into account the magnification. Some crystals (ie at least 5 crystals and advantageously at least 10 crystals)
And measure the average to avoid the risk of measuring atypical crystals or clusters of crystals.

First, the crystallization pattern may be qualitatively observed using an optical microscope under crosspolar conditions. If the initial observation indicates that the crystals are of an appropriate size, a microscope sizing test as described above is performed.

Melting point Furthermore, the melting point of the mixture is 40.
It must be selected in such an amount that it is in the range of 100C to 100C. The melting point must be within this range to ensure that the crystalline barrier is present during storage and that the oil phase releases during topical application. Advantageously, the melting point of the mixture ranges from 40C to 75C, most preferably 45C.
~ 55 ° C. Further, the melting point of the mixture of the fluid oil and the barrier component must be fairly sharp, ie, the components in the barrier component and the fluid oil must all be very compatible with each other. The difference in melting points must not be above 25 ° C., preferably not above 10 ° C., and most preferably, the melting point is determined by differential scanning calorimetry (DSC), It is a peak.

The barrier component (ie a mixture of at least two compounds forming the barrier layer) is present in the composition according to the invention in an amount of from 1 to 20% by weight of the emulsion, preferably from about 5 to about 15%, most preferably. Is used in an amount of about 8 to about 12% by weight.

As mentioned above, the barrier layer according to the invention is formed by the interaction of at least two compounds: a crystal-forming compound and a crystal-sizing compound. The crystal sizing compound is 1-75% by weight of the crystal forming compound, preferably 5%.
It is added in the order of ４０40% by weight, most advantageously of the order of 10-20% by weight.

Suitable crystal forming compounds for use in the emulsions of the present invention include, but are not limited to, fatty acids, mixtures of fatty acids and their soaps, fatty alcohols and ethoxylated derivatives of fatty acids or fatty alcohols, Sterols (eg lanolin or cholesterol)
And mixtures thereof. Advantageously, the crystalline form compound is selected from the group consisting of C ₁₂ -C ₂₂ (preferably C ₁₆ -C ₂₂₎ fatty acids or alcohols or ethoxylated derivatives and mixtures thereof. Most advantageously,
The crystal forming compound is selected from the group consisting of palmitic acid, stearic acid, stearyl alcohol, cetyl alcohol, behenic acid, behenyl alcohol, cholesterol and sorbitan stearate and mixtures thereof.

The crystal sizing compound is selected from the group consisting of hydroxylated fatty acids or alcohols (C ₁₂ -C ₂₂ ) and ethoxylated derivatives thereof. Preference is given to using hydroxylated fatty acids or alcohols or mixtures. Preferred chain lengths are C ₁₆ -C _22. Most advantageously, the crystalline sizing compound is selected from the group consisting of glyceryl monohydroxystearate, hydroxystearic acid, isostearyl alcohol, isostearic acid and mixtures thereof.

The crystal sizing compound may or may not be contained in the actual crystal forming the crystal barrier layer. Crystal sizing compounds regulate the size of the crystals, thus
As is essential in forming a suitable crystal barrier, the location may be in the crystal, in the oil drop, or in a combination of the two locations.

The relative size of the individual oil droplets to the individual crystals in the emulsion according to the invention is in the range from 5: 1 to 100: 1, preferably in the range from 5: 1 to 50: 1, most preferably Is in the range of 5: 1 to 20: 1. The size of the crystal is measured by a microscope crystal sizing test as described above. The size of the oil droplets also microscopic crystal Sizing Test or particle size analyzer (e.g., Masutesaiza ^R (Mastesizer)) can be measured using the.

The overall size of the particles formed from the oil droplets and the crystals surrounding the oil droplets is also important according to the invention.
The half-life of a retinoid in a particle is inversely proportional to the size of the particle. The larger the particles, the slower the retinoid diffusion. Also, the physical stability of the emulsion is affected if the particle size is too large. Therefore, the particle size must be such as to achieve the chemical stability of the retinoid and to maintain the physical stability of the emulsion. Due to the involvement of the present invention, the volume average particle size is 5 μm to 500 μm.
m, preferably in the range of 10 μm to 50 μm.

The particle size was measured by a particle size analyzer (Mastizer).
^R ) and by measuring the d (5.3) or d (4.3) average particle size as described in the Mastersizer Manual.

Other essential components of the emulsion of the present invention include:
In the aqueous phase. The aqueous phase of the emulsion according to the invention comprises at least 20% of water. However, a particular advantage of the emulsions of the present invention is that they may incorporate large amounts of water. Preferred emulsions are at least 40% water, preferably 40% to 95%
Of water, most preferably 60% to 70% water. The aqueous phase may optionally contain other water-soluble solvents or components. Particularly advantageous water-soluble components to be incorporated into the aqueous phase are hydroxy acids as described in more detail below. The total aqueous phase is advantageously at least 65% by weight of the emulsion, most advantageously at least 70% by weight.

The composition of the present invention has at least one
5 days, preferably 20-45 days, most preferably 35-45
Has a half-life of days.

"Half-life" is defined as the time it takes for a retinol or short-chain ester thereof to degrade to half its original concentration at a given temperature.

The advantageous compositions according to the invention are substantially free of lower-chain simple alcohols such as methanol, ethanol or propanol in order to avoid the drying and irritating effects of such alcohols on the skin.

The pH of the composition ranges from 2.5 to 10. Preferred compositions of the present invention have a pH from about 6 to about 9, and most preferably from about 6.5 to about 7.5.

It has been found that the emulsions of the present invention can be mixed with other emulsions, including multiple emulsions. Further, the emulsion of the present invention
The oil of the present invention may contain other oil droplets which do not contain the fluid oil (liquid oil) or the retinoid. As long as the oil phase comprises an oil-in-water emulsion containing about 0.1 to about 50% of the oil droplets, the composition is within the scope of the present invention.

Optional skin benefit materials and cosmetics
Tick additives Various types of skin benefit ingredients may be present in the cosmetic emulsions of the present invention. While not limited to this category, common examples include anti-wrinkle compounds and sunscreens and tanning agents.

A particularly advantageous optional component is a hydroxy acid. One of the advantages of the emulsions of the present invention is that high amounts of aqueous phase can be incorporated. Thus, generally high amounts of water-soluble active agents and especially hydroxy acids,
It may be present together with the retinoid activator.

Hydroxy acids are α-hydroxy acids, β-
It may be selected from hydroxy acids, other hydroxy carboxylic acids (eg, dihydroxy carboxylic acids, hydroxy dicarboxylic acids, hydroxy tricarboxylic acids) and mixtures thereof or combinations of their stereoisomers (DL, D or L).

Hydroxy acids are α-hydroxy acids, β-
Hydroxy acids (eg, salicylic acid), other hydroxycarboxylic acids (eg, dihydroxycarboxylic acid, hydroxydicarboxylic acid, hydroxytricarboxylic acid) and mixtures thereof or stereoisomers thereof (DL, D or L)
Can be selected from the following combinations:

Preferred hydroxy acids (ii) have the general formula (1)

[0047]

Embedded image

Wherein M is H or a saturated or unsaturated linear or branched hydrocarbon chain having from 1 to 27 carbon atoms, and is selected from α-hydroxy acids.

More advantageously, the hydroxy acid is selected from glycolic acid, lactic acid, 2-hydroxyoctanoic acid, hydroxylauric acid and mixtures thereof. When stereoisomers are present, the L-isomer is most advantageous.

[0050] Advantageously, the amount of hydroxy acid component present in the emulsion according to the invention is less than 0.1% of the emulsion.
01-20% by weight, more advantageously 0.05-12% by weight
And most preferably 0.5 to 8% by weight.

Sunscreens include those materials commonly used to block ultraviolet light. Illustrative compounds are derivatives of PABA, cinnamate and salicylate. For example, octyl methoxycinnamate and 2
-Hydroxy-4-methoxybenzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are trade names Parsol MCX and benzophenone-3, respectively.
Commercially available. The exact amount of sunscreen used in the emulsion may vary depending on the degree of protection desired from the sun's UV radiation.

An optional additional component in the cosmetic composition of the present invention is a thickener. Thickeners usually comprise from 0.1 to 20% by weight of the emulsion, preferably from 0.5 to 1%.
It is present in an amount of 0% by weight. Exemplary thickeners are available from Carbopol under the tradename Carbopol. F. Goodrich Company
a crosslinked polyacrylate material obtained from y). Gums such as xanthan, carrageenan, gelatin, karaya, pectin and carob gum may be used. Under certain circumstances, the viscous function may be completed by silicone or a material that also serves as an emollient. For example,
Esters such as silicone rubber and glycerol stearate in excess of 10 centistokes are bifunctional.

A powder may be incorporated into the cosmetic composition of the present invention. These powders are chalk,
Talc, fuller's earth, kaolin, starch, smectite clay, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof Is included.

[0054] Other minor additives may also be incorporated into the cosmetic composition. These ingredients include colorants, opacifiers and fragrances. The amount of these other minor additives may range from about 0.001% by weight of the emulsion.
It may vary at 20% by weight.

In addition, it is important to ensure that other components do not interfere with the position of the crystal, for example, high HLB
When using emulsifiers, the crystals can be broken.

Preparation of the Composition An advantageous method of preparing the composition of the invention involves the following steps: (1) providing an aqueous phase and heating to 75-80 ° C. with mixing; (2) An oil phase containing a liquid oil and a barrier component compound but not containing a retinoid is prepared, and mixed with 75 to 8 oils.
(3) slowly add the oil phase to the aqueous phase, with both phases at 75-80 ° C .; (4) mix the mixture obtained in step (3) with 75-80 ° C. (5) After cooling the mixture to 50-55 ° C, add the retinoid with mixing; (6) Fill into storage containers.

If the final composition contains a hydroxy acid, the hydroxy acid is advantageously added after step (4) to 5
At 0-60 ° C, add separately.

Use of the compositions The compositions according to the invention are mainly used as products for topical application to human skin, in particular for conditioning and smoothing the skin and for the appearance of dry, wrinkled or aged skin. It is intended as an agent for preventing or reducing. In use, a small amount, e.g., 1-100 ml, of the composition is applied from a suitable container or applicator to the exposed surface of the skin, and if necessary, then, using a hand or finger or a suitable device Spread and / or rub on skin.

Product Form and Packaging Emulsions of the present invention can be used in lotions, liquid creams,
It can be formulated as a cream or gel. The composition can be filled in a suitable container according to its viscosity and intended use by the consumer. For example, a lotion or liquid cream can be filled into a bottle or a rollball applicator or capsule or container with a propellant-driven aerosol device or a pump suitable for finger operation. When the composition is a cream, it can be conveniently stored in a non-deformable container or a squeezed container such as a tube or lidded jar.

The present invention therefore also provides a closed container containing a cosmetically acceptable composition as described above.

[0061]

The following specific examples further illustrate the present invention.

[0062] to produce a composition to be stability evaluation test, filled into jars or high density polyethylene (HDPE) tube. Seal the jar or tube and store at 30 ° C, 41 ° C or 5 ° C for storage.
Placed in 0 ° C. oven. The stability study performed at 50 ° C. was an accelerated stability study. Half life is 50 ° C: 3
It is temperature dependent at a ratio of 1: 6: 9: 18 at 0 ° C: 25 ° C: 20 ° C. For example, a half life of 40 days at 50 ° C. is 30
8 months at 25 ° C, 1 year at 25 ° C (standard room temperature) and 2 at 20 ° C
Equivalent to year. In addition, stability studies were facilitated by storage of samples under adverse conditions in the presence of excess oxygen as described below. For optimal stability in commercial samples,
We recommend placing the system in an inert atmosphere of argon (advantageously) or nitrogen. In the absence of excess air, retinol stability is increased by at least a factor of two. For stability studies performed under aerated conditions, tubes or jars were filled 1/3 with the composition, took up 2/3 headspace and aerated at each time point. The composition is analyzed at regular time intervals until less than 10% of the initial retinol remains unoxidized.

The stability studies in the following examples were performed under aerated conditions.

Our work has shown that retinol oxidation in the compositions evaluated for the present invention is dependent on the first order kinetics of retinol concentration.
c). Therefore, to determine the reaction half-life, the natural log of retinol concentration (InC) is plotted against storage time (t) and a straight line with slope k is obtained, where k is the inverse of time Unit (re
retinol oxidation rate in a ciprocal unit). The half-life of retinol in the system in the study (t1 / 2) is then determined by the In2 / k ratio.

Analysis of Retinol by HPLC All samples were analyzed by high pressure liquid chromatography (hardware: Waters 600-MS system controller).
waters 717 autosampler, Waters 717 autosampler
ler), Waters 996 photodiode array detector (Waters 966 photo)
diode array detector), software: Millenium 2010)
Was used to analyze for retinol content. The column parameters used for retinol analysis were as follows: Column: Nucleosyl C18 5 μm (Sigma
a-Aldrich) 250 mm x 4.6 mm Catalog #: Z226181

Injection volume: 10 μl Flow rate: 1 ml / min Operating time: 10 minutes Detector: 325 using photodiode array
UV / visible in nm Residence time: about 5 minutes for retinol.

Standard Solution Preparation A standard curve was generated each time a sample was analyzed for retinol content. Retinol standards were prepared by serially diluting the retinol blend in isopropanol to a final concentration of 0, 10, 20, 30, 40 and 50 p.
A standard solution with pm (w / w) was obtained. Standard solutions were prepared weekly and stored at -21 ° C.

Sample Preparation Most samples were prepared by simple dilution in isopropanol, so that the final retinol concentration was within the standard curve, preferably about 30 ppm.

Emulsion samples such as thick creams containing rubber are more difficult to manufacture. To ensure complete extraction of retinol from the emulsion, the sample was processed in the following way: about 0.5 g of the accurately measured sample was first mixed with 6-7 g of water and a vortex was formed, Was formed. Then about 10 g of isopropanol was added to the slurry, followed by a second vortex step. The sample was then brought to final weight with isopropanol. Subsequently, the sample was filtered using a disposable syringe equipped with a 0.2 μm disposable filter.

All samples were analyzed w / w using an analytical balance.
Three or five bases were manufactured.

Analysis of Retinyl Acetate by HPLC The same method and the same mobile phase as for retinol are used.
Retinyl acetate elutes about 30 seconds after retinol.

Example 1 Compositions 1 , 2 and 3 (all within the scope of the invention) were prepared.

[0073]

[Table 1]

The following procedure was used to prepare the composition: 1. Heat aqueous phase (A) to 75-80 ° C while mixing in an overhead mixer. 2. Heat oil phase (B) to 75-80 ° C while mixing. 3. Add oil phase (B) slowly to aqueous phase (A) with both phases at 75-80 ° C. Use water from (C) heated to 75-80 ° C. to wash off oil phase residues 5. At 75-80 ° C. for at least 15 min. Mix 6. 6. Start cooling Prepare phase (D) at room temperature and add (ABC)
7. Add at 60 ° C. 9. Add retinol blend (E) to batch at 50 ° C to 55 ° C with mixing 9. Mix while cooling to 40 ° C. 10. Add (F) at 40 ° C. with mixing Stop mixing and fill into storage container.

Observation: Compositions 1, 2 and 3 were substantially
Had similar properties when viewed under a light microscope: surrounded by a crystal barrier layer as determined by the presence of a bright birefringent circle around each droplet when viewed under cross-polar A spherical oil droplet about 50 microns in diameter. This was evidenced by the fact that the bulk aqueous phase was substantially free of individual crystals.
Using microscopic crystal sizing tests, the crystals were found to be regularly shaped and about 8 microns in diameter.

Comparative Example 2 Comparative compositions A, B, C, D, E, F and G (all outside the scope of the invention) were prepared:

[0077]

[Table 2]

The retinol blend was completely soluble or readily dispersible in AG.

Compositions AG contained no barrier components.

The storage stability of Compositions 1-3 (Example 1) and Comparative Compositions A-G was determined by the method described above (using an aeration test). The results obtained are summarized in Table 1, Table 1A and Table 1B.

[0081]

[Table 3]

[0082]

[Table 4]

[0083]

[Table 5]

Observations: Storage stability measurements of Compositions A and B (Table 1A) show that retinol is more stable in an oil environment (composition A) than in an aqueous environment (composition B). Shown: t1 / 2 of A is 34 days (30 days) at 50 ° C.
297 days at 50 ° C. vs. t1 / 2 of B at 50 ° C. for 2 days (30 ° C.)
24th). Surprisingly, Compositions 1-3 showed similar retinol stability as retinol in mineral oil (Composition A): t1 / 2 of 2, 2 and 3 was 20 at 50 ° C, respectively.
Days, 39 days and 20 days, 120 days at 30 ° C. respectively, 2
60 days, 149 days. Considering the fact that these systems contain an 80% w / w continuous aqueous phase, the retinol stabilization of compositions 1-3 is significant. Retinol is stable because it is held in a separate oil microenvironment within the emulsion by the presence of the interfacial crystal barrier of the present invention.

Compositions C-G were prepared in a polar environment such as Tween 20, butylene glycol, glycerin or decyl alcohol (t1 / 2 is 90 ° C.).
At 36 hours, 14 hours, 19 hours and 25 hours respectively) than in nonpolar environments such as mineral oil (t1 /
2 for 90 hours at 90 ° C.). Because retinoids are less stable the more polar the environment, we can understand why retinol or short-chain retinol esters are less stable in aqueous emulsion systems than long-chain esters such as retinyl palmitate. . Retinol or short-chain retinol esters are more polar than long-chain esters such as retinyl palmitate, and when they are more polar, they are more advantageous in polar solvents such as water than long-chain esters. Has a tendency to be distributed. The more they are distributed from the oil into the polar solvent, the more unstable they are, which explains why retinyl palmitate is more stable in emulsion systems than retinol or retinyl acetate. (B. Idson, C & T, Vol 10
Pages 8, 86: "Vitamin A palmitate is the most stubble of available vitamin A esters (Vitamin A palmitat)
e is the most stable of a
available vitamin A ester
s) ", Roche:" Retinol is
More Sensitive Than Fatty Acid
Esters of Vitamin A (retinol is
More Sensitive Than Fatty
acid esters of vitamin
A) ").

Comparative Example 3 Compositions G1 and H (both outside the scope of the invention) were prepared. Both compositions contain retinol capsules, ie, the cured polyacrylic acid / capsules forming the capsules.
The retinol in the petroleum jelly was dispersed in the carrageenan gel, which was then dispersed in the final composition G1 or H (when cold). The resulting composition was outside the scope of the present invention.

Composition of Retinol Capsule A Snow Vaseline 17.1% A Retinol Blend 3.1% B Aculin 33 solution (4% neutralized to pH 7) 45.3% B Gelcarin 6P-911 ( (Kappa carrageenan) 34.5% capsule production: 40 retinol and snow petrolatum
Mix at ４５45 ° C. to form phase A. Accurin 33 (polyacrylic acid) solution previously neutralized to pH 7
Heat to ~ 70 ° C and add carrageenan. Add B to A and emulsify at 650 rpm for 4 minutes using low shear homogenization (eg, Denver flotation apparatus). Capsules are made by pouring the emulsion drop by drop into a curing bath consisting of 10% KCL and 0.5% Triton X-100.
The capsules were then dried on filter paper, weighed and added cold to the concentrated emulsion of the invention by gentle manual stirring. The other components listed in Table 2 were added cold with gentle agitation. The retinol content in both compositions G1 and H was 0.1% at the beginning of the storage period.
%.

[0088]

[Table 6]

Compositions G1 and H contained barrier components such as Composition 1 of Example 1, but those components did not serve as a barrier layer around retinol. This is because retinol capsules were subsequently added to composition 1 to produce compositions G1 and H.
Both compositions G1 and H contained retinol solubilized in the fluid oil phase, but this oil phase was not surrounded by the combination of barrier components forming the crystalline barrier layer according to the invention. Fluorescence micrographs showed that retinol was located within the Vaseline phase of the capsule. Light microscopy did not show the presence of a uniform interfacial barrier, but showed the presence of randomly dispersed crystals in petrolatum.

The storage stability of compositions G1 and H was determined by the method described above (using an aeration test). The results obtained are summarized in Table 3.

[0091]

[Table 7]

The storage stability results in Table 3 were compared to the storage stability of Compositions 1 and 2 in Table 1. Compositions G1 and H
Compositions 1 and 2 contained the barrier component around the retinol droplet, as compared to

In the absence of the barrier component of the present invention around the retinol droplet, the half-life at 50 ° C. is from 20 days for composition 1 to 6 days for composition G1; The thing H decreased on the 12th. This is evidence of an important role for the presence of barrier components around retinol droplets in stabilizing retinoids in the compositions of the present invention.

This example also demonstrates the criticality of using the method of the present invention in making the composition of the present invention.

Comparative Example 4 Composition K was prepared (outside the scope of the invention). This composition contained a crystal sizing compound in the barrier component but no crystal forming compound. Composition K comprises composition 1 (pH = 10) except that the crystal forming compounds, stearic acid and stearyl alcohol, are not present in composition K.
It was the same as 3.6).

The storage stability of Composition K was determined by the method described above (using an aeration test). Table 4 shows the obtained results.
Put together.

[0097]

[Table 8]

The storage stability results in Table 4 were measured for Compositions 1 and 2.
Was compared with the storage stability (Table 1). In the absence of the crystal-forming compound of the present invention, the half-life was reduced from 20 days (composition 1) at 50 ° C. to 4 days (composition K). This is evidence of an important role of crystal forming compounds in stabilizing retinoids in the compositions of the present invention. Microscopic observation of composition K showed the presence of very small crystals of less than 1 micron in diameter (outside the scope described by the claims of the invention).

Comparative Example 5 Composition L was prepared (outside the scope of the invention). This composition contained a crystal forming compound in the barrier component, but did not contain a crystal sizing compound.

First, at 500 rpm at 45 to 55 ° C., 15
A retinol concentrate was made by adding B to A at 73 ° C. with mixing for minutes. This concentrate was then added to Composition 1 without phases D and E at 35-40 ° C., resulting in a retinol concentration of about 0.1%. Alpha hydroxy acid was added to obtain pH = 3.6.

Retinol concentrate: A Water DI 59.25% A Celtrol 1000 0.5% A TEA (99%) 0.25% B Behenic acid 12% B ISP 20% B Retinol blend 8% Composition L: Modified Composition 1 74.96% water DI 5% glycolic acid (70%) 11.4% ammonium hydroxide (29%) 2.5% hydroxycaprylic acid 0.1% retinol concentrate 3.3% water DI 2 0.51% bis-aborole 0.2% fragrance 0.03% The storage stability of Composition L was measured. Table 5 shows the obtained results.
Put together.

[0102]

[Table 9]

In the absence of the crystal sizing compound, the half-life was reduced from 20 days (Composition 1) to 8 days (Composition L) at 50 ° C. respectively. This is evidence of an important role of crystalline sizing compounds in stabilizing retinoids in the compositions of the present invention.

The deficiency of the crystal sizing compound was revealed by the presence of large, irregularly sized crystals (about 60 microns in diameter) when observed under a microscope.

Comparative Example 6 Compositions M and N were prepared (outside the scope of the invention). This composition contained a flowable oil (high molecular weight silicone oil) that was incompatible with retinol.

First, an incompatible oil (Dow)
A concentrated retinol dispersion in (high molecular weight silicone oil) was prepared. The concentrate is then heated at 50-55 ° C.
When added to Composition 1 without Phases D and E, a retinol concentration of about 0.05% was obtained.

Retinol concentrate dispersion: Dow 200 10000 cst fluid 79.4% cab-o-sil TS720 (silica) 9% Retinol blend (Roche) 11.6% Composition M: Modified Composition 1 74.96% water DI 16.8% retinol concentrate dispersion 8% bisabolol 0.2% fragrance 0.03% pH 7.4 Composition N: modified composition 1 74.96% water DI 2.81% glycolic acid (70%) 11.4% ammonium hydroxide (29%) 2.5% hydroxycaprylic acid 0.1% retinol concentrate dispersion 8% bisabolol 0.2% fragrance 0.03% pH 3.7 Storage of compositions M and N Stability was measured. The results obtained are summarized in Table 6.

[0108]

[Table 10]

In the absence of the retinoid compatible oils of the present invention,
Half-life is 20 days (composition 1) to 4 days (composition N) and 39 days (composition 2) to 13 days (composition M) at 50 ° C.
Decreased to. The retinoids remain undispersed in the oil phase of the modified composition 1 by using silica to trap the retinoids into silicone droplets that are insoluble as revealed by light microscopy. (Retinol was dispersed as discrete droplets in the high molecular weight silicone, but Retinol did not solubilize). This is evidence of an important role of fluid oils in stabilizing retinoids in the compositions of the present invention.

Example 7 Purpose The purpose of this study was to evaluate the efficacy of the following formulations: 1. 8% L-lactic acid versus 8% L-lactic acid / 0.174% retinyl acetate (both in emulsion base) 2. 8% L-lactic acid to 8% L-lactic acid / 0.25% retinyl palmitate (both in emulsion base) 8% L-lactic acid / 0.075% retinol vs. 8% L
-Lactic acid / 0.09% retinyl acetate (both in emulsion base) Treatment group 1 had 16 female subjects (age 45 and over) and groups 2 and 3 each had 17 subjects .

These formulations are not within the scope of the present invention: this study was performed solely to confirm the relative potency of retinol vs. retinyl acetate vs. retinyl palmitate, and did not confirm stability. Not to do.

[0112]

[Table 11]

[0113] Within each treatment group, the test products were randomized left / right. Subjects applied the test product at home twice daily (morning and evening) for 12 weeks. The test was performed double blind. Medium creepiness on the forearm (crepi
50 female subjects with essence (wrinkled appearance) participated. Subjects continued on a regular clean-up routine, but were instructed not to apply any moisturizing product to their forearms and hands for one week prior to the baseline visit (week 0). At baseline, 2, 4, 8, and 12 weeks,
A visual evaluation was made (evaluation included assessment of the crepe state and overall appearance). Whenever possible, evaluations were made in the same place under constant lighting. All products were weighed at each visit to determine compliance.

Assessment: Clinical Evaluation The following parameters were evaluated by trained assessors.

Outer forearm: crepe / wrinkled skin -loose / loose surface / lined / wrinkled skin (improvement is more firm, less wrinkled / wrinkled) Showing untouched skin).

Overall Appearance (Light Damage) -An overall assessment of the condition of the area with respect to touch and overall surface features (improvement indicates better overall skin condition).

0-9 of crepe / wrinkled skin
A point rating scale was used: mild 1 to 3 small, annular fine lines not seen at all at first sight; looks better when twisting skin Moderate 4 to 6 clear lines less than 25% of lower outer forearm / back of hand Inlaid pattern, annular line with "puffy" appearance Range of more than 25% but very clear up to 100% range of all outer forearms / non-back altitudes 7-9 outer lower forearms / backs Long, bulging (depth) vertical lines, well bounded, mid-to-category degrees were assigned for responses that do not guarantee complete category gain.

Neither the assessor nor the study subjects knew the identity of the formulation tested.

Statistical analysis Raw data were collected from Wilcoxon signed-rank,
Platform version (Wilcoxon Signe
d-Rank, Pratt version)
AS-based macro computer program% WS
Analysis was performed using IGNRNK.

Statistical analysis was performed separately for each paired product control, test site (outer forearm, back of hand), time of evaluation and attribute measurements. Paired control statistical analysis was performed for each treatment group. Differences were considered statistically significant at p> 95%.

The clinical assessment among the treatment controls is shown in Table 7A below.
Table 7C summarizes.

[0122]

[Table 12]

[0123]

[Table 13]

[0124]

[Table 14]

Results: The composition containing 8% L-lactic acid and 0.25% retinyl palmitate did not give a noticeable improvement in creped arm skin over 8% L-lactic acid in the same base formulation. Was. Conversely, 8% L-lactic acid and 0.
The same base formulation containing 17% retinyl acetate is better than 8% L-lactic acid in the same base formulation (p at 8 weeks).
> 95%), both scoring and forced selection (results of the latter are not shown here) resulted in clearly clinically confirmed improvements in crepe skin. further,
The same base formulation containing 8% L-lactic acid and 0.075% retinol is better than 8% L-lactic acid and 0.09% retinyl acetate (p> 12 weeks) in the same base formulation.
95%), both ratings and forced selection resulted in a clearly clinically confirmed improvement in crepe skin.

In conclusion, retinyl palmitate did not increase the anti-aging efficacy of the hydroxy acid formulation, while retinyl acetate did. Retinol is the most advantageous retinoid to be used in the present invention, since this efficacy is further improved when retinol is used instead of retinyl acetate.

Example 8 The following additional compositions within the scope of the present invention were prepared. This composition was produced by the method of the present invention. This is suitable for cosmetic use. In particular, this composition is suitable for application to wrinkled, lined, rough, dry, flaky, aged and / or UV-damaged skin to improve its appearance and feel. And suitable for application to healthy skin to prevent or delay its deterioration.

[0128]

[Table 15]

[0129]

[Table 16]

Continued on the front page (72) Inventor Prem Chiyander United States, New Jersey 07624, Kloster, Smith Court 24 (72) Inventor Mark Edward Riark United States, New Jersey 07076, Scotch Plains, Concord De Lord 2316

Claims (10)

[Claims] 1. A stable oil-in-water emulsion for a skin conditioning composition, wherein the emulsion comprises: (a) 0.1-50% by weight of the emulsion, oil droplets composed of flowing oil, and 0% of the emulsion. .01-10
By weight of an oil phase comprising a retinoid selected from the group consisting of retinol, retinyl acetate and retinyl propionate, wherein the retinoid is solubilized in the oil; (b) 50-98 of the emulsion (C) 1-20% by weight of the emulsion, comprising a crystal forming compound and a crystal sizing compound, wherein the barrier component comprises a crystal barrier between the oil droplets and the aqueous phase. Wherein the average size of the individual crystals in the barrier layer is in the range from 1 μm to 50 μm, as determined by microscopic crystal sizing; The ratio of the size of individual crystals in the oil hostile barrier layer is 5:
An oil-in-water emulsion, wherein the melting point of the mixture of the fluid oil and the barrier component is in the range of 40 ° C to 100 ° C. 2. The crystal forming compound is a C ₁₂ -C ₂₂ fatty acid,
Mixture of its soaps C ₁₂ -C ₂₂ fatty acids, C ₁₂ -C ₂₂
Fatty alcohols, C ₁₂ -C ₂₂ is selected from fatty acids and C ₁₂ -C ₂₂ ethoxylated derivatives of fatty alcohols and mixtures thereof, according to claim 1 emulsion according. 3. The crystalline sizing compound is selected from the group consisting of hydroxylated fatty acids, hydroxylated fatty alcohols, and ethoxylated derivatives thereof, and mixtures thereof. The emulsion as described. 4. The fluid oil of claim 1, wherein the oil is selected from the group consisting of isostearyl palmitate, tridecyl salicylate, C ₁₂ -C ₁₅ octanoate, isopropyl stearate, isopropyl myristate, and isopropyl palmitate. The emulsion according to any one of claims 1 to 3. 5. The method of claim 1, wherein the retinoid is selected from the group consisting of retinol and retinyl acetate.
The emulsion according to any one of the above. 6. The emulsion according to claim 1, wherein the emulsion contains at least 40% of water. 7. The emulsion according to claim 1, wherein the aqueous phase of the composition contains an alpha hydroxy acid. 8. The emulsion according to claim 1, wherein the half-life of the composition at 50 ° C. is at least 15 days. 9. A method for producing a stable oil-in-water emulsion according to any one of claims 1 to 8, comprising the steps of: (1) preparing an aqueous phase and mixing at 75 to 80 ° C while mixing. (2) preparing a mixture containing the fluid oil and the barrier component compound, and heating the mixture to a temperature in the range of 75 to 80 ° C. while mixing the mixture; (4) mixing the mixture obtained in step (3) at a temperature in the range of 75-80 ° C. for at least 15 minutes; (5) mixing the mixture obtained in step (4) After cooling to a temperature in the range of 50 to 55 ° C., and then adding the retinoid while mixing; (6) a method for producing an emulsion, which comprises filling in a storage container. 10. Further, after step (4), 50 to 6
10. The method of claim 9, comprising adding the hydroxy acid at a temperature in the range of 0 <0> C.